Abstract 1905: New targeted therapeutics for gastric cancer

Abstract

Abstract Gastric cancer is a health disparity with 2.3 times higher incidence rates in Hispanics than in Non-Hispanic Whites (NHWs). Very few studies have been conducted to characterize this health disparity in Hispanics; however, studies from East Asian patients, where gastric cancer is also a health disparity, have revealed that p21-activated kinases (PAKs 1,2 and 4) are biomarkers for gastric cancer. Even though inhibition of PAKs impedes gastric cancer progression, current PAK inhibitors have failed to successfully complete clinical trials. Thus, we hypothesize that the inhibition of upstream effectors of PAK, the Rho GTPases Rac and Cdc42 is a rational treatment for gastric cancers with high PAK expression. The purpose of this study is to correlate Rac/Cdc42 and PAK expression and activation with Hispanic gastric cancer malignancy, and to test the efficacy of our recently developed Rac/Cdc42 inhibitor MBQ-167 (Humphries-Bickley, et al., Mol Cancer Therap. 2017, 16:805-818). In a related Aim, to identify new targets and biomarkers for Hispanic gastric cancer, gastric cancer tissues and normal gastric mucosa from biopsies and/or surgery were collected from Puerto Rican patients for expression profiling with customized qRT-PCR arrays for mRNA and Agilent arrays for non-coding RNAs (ncRNAs), and western blotting. Western blotting of gastric cancer cell lines revealed that NCI-N87 metastatic gastric cancer cells express more PAK isoforms and phospho (active)-PAK compared to the AGS non-metastatic gastric cancer cells; accordingly, MBQ-167 reduces the viability of NCI-N87 cells without affecting AGS cells. Therefore, to test the efficacy of Rac/Cdc42 inhibition in gastric cancer, immunocompromised mice with subcutaneous tumors from GFP-NCI-N87 cells were treated 3X week with vehicle or 1mg/kg BW of MBQ-167. Tumor growth calculated by image J analysis of fluorescent digital images. A drastic reduction in NCI-N87 tumor growth was observed in the MBQ-167 treated mice with a 61% inhibition in tumor size compared to the controls, and a tumor growth delay of >90% after the second doubling time. Gene expression profiling revealed that 13 genes were overexpressed (>1.5 fold change) in Puerto Rican gastric cancer tissue in comparison to the normal gastric mucosa, including Rac1, PAK1, STAT3, KDR (VEGFR2), CXCR4, IGF1, VEGFA, and IL-6, all of which are associated with Rac/Cdc42/Pak signaling. Differential profiling using a custom-made Agilent array for ncRNAs demonstrated upregulation of a number of pro-cancer microRNAs (miRNAs) such as miR-106b and downregulation of tumor suppressors such as let-7a and miR-145, as well as upregulation of the long ncRNA CCAT2, which we have shown to be important for colon cancer malignancy. Taken together, our data show that Hispanic gastric cancers have known and novel biomarkers, and MBQ-167 is a viable targeted therapeutic option for gastric cancers with elevated Rac/Cdc42/PAK signaling. Citation Format: Jean F. Ruiz Calderon, Marcia Cruz-Correa, George A. Calin, Linette Castillo-Pichardo, Suranganie Dharmawardhane. New targeted therapeutics for gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1905.